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ABSTRACT The Enterobacteriaceae are a scientifically and medically important clade of bacteria, containing the model organism Escherichia coli, as well as major human pathogens including Salmonella enterica and Klebsiella pneumoniae. Essential gene sets have been determined for several members of the Enterobacteriaceae, with the Keio E. coli single-gene deletion library often regarded as a gold standard. However, it remains unclear how gene essentiality varies between related strains and species. To investigate this, we have assembled a collection of 13 sequenced high-density transposon mutant libraries from five genera within the Enterobacteriaceae. We first assess several gene essentiality prediction approaches, investigate the effects of transposon density on essentiality prediction, and identify biases in transposon insertion sequencing data. Based on these investigations, we develop a new classifier for gene essentiality. Using this new classifier, we define a core essential genome in the Enterobacteriaceae of 201 universally essential genes. Despite the presence of a large cohort of variably essential genes, we find an absence of evidence for genus-specific essential genes. A clear example of this sporadic essentiality is given by the set of genes regulating the σE extracytoplasmic stress response, which appears to have independently acquired essentiality multiple times in the Enterobacteriaceae. Finally, we compare our essential gene sets to the natural experiment of gene loss in obligate insect endosymbionts that have emerged from within the Enterobacteriaceae. This isolates a remarkably small set of genes absolutely required for survival and identifies several instances of essential stress responses masked by redundancy in free-living bacteria.IMPORTANCEThe essential genome, that is the set of genes absolutely required to sustain life, is a core concept in genetics. Essential genes in bacteria serve as drug targets, put constraints on the engineering of biological chassis for technological or industrial purposes, and are key to constructing synthetic life. Despite decades of study, relatively little is known about how gene essentiality varies across related bacteria. In this study, we have collected gene essentiality data for 13 bacteria related to the model organism Escherichia coli, including several human pathogens, and investigated the conservation of essentiality. We find that approximately a third of the genes essential in any particular strain are non-essential in another related strain. Surprisingly, we do not find evidence for essential genes unique to specific genera; rather it appears a substantial fraction of the essential genome rapidly gains or loses essentiality during evolution. This suggests that essentiality is not an immutable characteristic but depends crucially on the genomic context. We illustrate this through a comparison of our essential genes in free-living bacteria to genes conserved in 34 insect endosymbionts with naturally reduced genomes, finding several cases where genes generally regarded as being important for specific stress responses appear to have become essential in endosymbionts due to a loss of functional redundancy in the genome.

Abstract A soil bacterium in the Serratia genus, carrying a 153 kb conjugative amber disease‐associated plasmid (pADAP), is commercially exploited for population control of the New Zealand endemic pest beetle Costelytra giveni (Coleoptera: Scarabaeidae). The main insecticidal elements are an anti‐feeding prophage and the Sep ABC toxin complex (Tc). Homologs of pADAP, encoding variant Tcs, convey different beetle disease phenotypes. To investigate the correlation between variable bioactivity and the Tc variant, 76 Serratia plasmids were sequenced, resulting in the identification of four additional tc variants. All Serratia tc variants were found to be colocated with a conserved type 1 sef fimbrial‐like operon, indicating a conserved sef‐tc genetic island not observed outside of the Serratia genus. The conserved co‐location of the fimbrial and tc genes suggests the fimbriae somehow contribute to the lifestyle of Tc‐producing cells. Expression of the sef operon in a fim‐null Escherichia coli strain revealed fimbriae presence while a constructed sef‐deficient mutant showed no reduction of virulence or host colonization. Although no detectable contribution of Sef to amber disease in C. giveni was observed, the Sef adhesin sequences clustered similarly to the Serratia species encoding it, suggesting Sef has a species‐specific function.

Abstract Background Computational biology provides software tools for testing and making inferences about biological data. In the face of increasing volumes of data, heuristic methods that trade software speed for accuracy may be employed. We have studied these trade-offs using the results of a large number of independent software benchmarks, and evaluated whether external factors, including speed, author reputation, journal impact, recency and developer efforts, are indicative of accurate software. Results We find that software speed, author reputation, journal impact, number of citations and age are unreliable predictors of software accuracy. This is unfortunate because these are frequently cited reasons for selecting software tools. However, GitHub-derived statistics and high version numbers show that accurate bioinformatic software tools are generally the product of many improvements over time. We also find an excess of slow and inaccurate bioinformatic software tools, and this is consistent across many sub-disciplines. There are few tools that are middle-of-road in terms of accuracy and speed trade-offs. Conclusions Our findings indicate that accurate bioinformatic software is primarily the product of long-term commitments to software development. In addition, we hypothesise that bioinformatics software suffers from publication bias. Software that is intermediate in terms of both speed and accuracy may be difficult to publish—possibly due to author, editor and reviewer practises. This leaves an unfortunate hole in the literature, as ideal tools may fall into this gap. High accuracy tools are not always useful if they are slow, while high speed is not useful if the results are also inaccurate.

Ribosome-targeting antibiotics comprise over half of antibiotics used in medicine, but our fundamental knowledge of their binding sites is derived primarily from ribosome structures of non-pathogenic species. These include Thermus thermophilus, Deinococcus radiodurans and the archaean Haloarcula marismortui, as well as the commensal and sometimes pathogenic organism, Escherichia coli. Advancements in electron cryomicroscopy have allowed for the determination of more ribosome structures from pathogenic bacteria, with each study highlighting species-specific differences that had not been observed in the non-pathogenic structures. These observed differences suggest that more novel ribosome structures, particularly from pathogens, are required for a more accurate understanding of the level of diversity of the entire bacterial ribosome, with the potential of leading to innovative advancements in antibiotic research. In this study, high accuracy covariance and hidden Markov models were used to annotate ribosomal RNA and protein sequences respectively from genomic sequence, allowing us to determine the underlying ribosomal sequence diversity using phylogenetic methods. This analysis provided evidence that the current non-pathogenic ribosome structures are not sufficient representatives of some pathogenic bacteria, such as Campylobacter pylori, or of whole phyla such as Bacteroidota (Bacteroidetes).

Introduction: The optimal surgical treatment for giant pituitary neuroendocrine tumors(GPitNETs) is debated. Research question: The aim of this paper is to optimize the surgical management of these patients and to provide a consensus statement on behalf of the EANS Skull Base Section. Material and methods: We constituted a task force belonging to the EANS skull base committee to define some principles for the management of GPitNETs. A systematic review was performed according to PRISMA guidelines to perform a meta-analysis on surgical series of GPitNETs. Weighted summary rates were obtained for the pooled extent of resection and according to the surgical technique. These data were discussed to obtain recommendations after evaluation of the selected articles and discussion among the experts. Results: 20articles were included in our meta-analysis, for a total of 1263 patients. The endoscopic endonasal technique was used in 40.3% of cases, the microscopic endonasal approach in 34% of cases, transcranial approaches in 18.7% and combined approaches in 7% of cases. No difference in terms of gross total resection (GTR) rate was observed among the different techniques. Pooled GTR rate was 36.6%, while a near total resection (NTR) was possible in 45.2% of cases. Cavernous sinus invasion was associated with a lower GTR rate (OR: 0.061). After surgery, 35% of patients had endocrinological improvement and 75.6% had visual improvement. Recurrent tumors were reported in 10% of cases Discussion and conclusion: After formal discussion in the working group, we recommend the treatment of G-PitNETs tumors with a more complex and multilobular structure in tertiary care centers. The endoscopic endonasal approach is the first option of treatment and extended approaches should be planned according to extension, morphology and consistency of the lesion. Transcranial approaches play a role in selected cases, with a multicompartmental morphology, subarachnoid invasion and extension lateral to the internal carotid artery and in the management of residual tumor apoplexy.

Background: Pituitary adenomas represent the most common pituitary disorder, with an estimated prevalence as high as 20%, and they can manifest with hormone hypersecretion or deficiency, neurological symptoms from mass effect, or incidental findings on imaging. Transsphenoidal surgery, performed either microscopically or endoscopically, allows for a better extent of resection while minimising the associated risk in comparison to the transcranial approach. Endoscopy allows for better visualisation and improvement in tumour resection with an improved working angle and less nasal morbidity, making it likely to become the preferred surgical treatment for pituitary neoplasms. The learning curve can be aided by telementoring. Methods: We retrospectively analysed the clinical records of 94 patients who underwent an endoscopic endonasal resection of a pituitary neoplasm between the years 2011 and 2023 at Maribor University Medical Centre in Slovenia. Remote surgical telementoring over 3 years assisted with the learning curve. Results: The proportion of complication-free patients significantly increased over the observed period (60% vs. 79%). A gradual but insignificant increase in the percentage of patients with improved endocrine function was observed. Patients’ vision improved significantly over the observed period. By gaining experience, the extent of gross total tumour resection increased insignificantly (67% vs. 79%). Conclusions: Telementoring for the endoscopic endonasal approach to pituitary neoplasms enables low-volume centres to achieve efficiency, decreasing rates of postoperative complications and increasing the extent of tumour resection.

Abstract Background Acromegaly is a disease of growth hormone excess that results in enlargement of extremities, abnormal glucose and lipid metabolism, and gonadal disruption. Manifestations of the disease are insidious and typically lead to a diagnostic delay of 7–10 years. Classically the polycystic ovary syndrome (PCOS) phenotype is described in women with irregular menses, clinical or biochemical evidence of androgen excess, and/or multiple ovarian follicles on pelvic ultrasonography. Women with acromegaly may present with some or all of these symptoms. Our objective was to evaluate the prevalence of PCOS in patients with acromegaly and to determine if diagnosis of PCOS results in a delay in diagnosing acromegaly. Methods Using patient databases at two academic health centers, we identified 97 premenopausal women aged 18–49 years old presenting with acromegaly. Data were collected regarding pelvic sonography and reproductive history, including the diagnosis of PCOS. Patients carrying the diagnosis of PCOS before their diagnosis of acromegaly were identified and the remaining patients were screened using the Rotterdam criteria to identify additional patients meeting the criteria for PCOS prior to their diagnosis of acromegaly. Results Mean age of the population (n = 97) at the time of diagnosis of acromegaly was 33.4 ± 7.5 years (SD). Thirty-three percent of patients (n = 32) either carried a diagnosis of PCOS or met diagnostic criteria for PCOS before their diagnosis of acromegaly. In the subset of patients in whom data on symptom onset were available, those who met criteria for PCOS were diagnosed with acromegaly a median of 5 years [4, 9] after the onset of symptoms compared to 2 years [0.92, 3] (p = 0.006) in the patients who did not meet criteria for PCOS. Conclusions Our data demonstrate a high prevalence of signs and symptoms of PCOS in reproductive-aged women with acromegaly and a longer time to diagnosis in women who meet the clinical criteria for PCOS. As screening for acromegaly is relatively simple and done with measurement of a random, non-fasting IGF-1 level that can be drawn at any time during the menstrual cycle, screening patients with PCOS for acromegaly may lessen the delay in diagnosis for reproductive-aged women with this disease.

Pseudomonas aeruginosa is an opportunistic pathogen that causes a wide range of problematic infections in individuals with predisposing conditions. Infections can be treated with colistin but some isolates are resistant to this antibiotic. To better understand the genetic basis of resistance, we experimentally evolved 19 independent resistant mutants from the susceptible laboratory strain PAO1. Whole genome sequencing identified mutations in multiple genes including phoQ and pmrB that have previously been associated with resistance, pitA that encodes a phosphate transporter, and carB and eno that encode enzymes of metabolism. Individual mutations were engineered into the genome of strain PAO1. Mutations in pitA, pmrB and phoQ increased the minimum inhibitory concentration (MIC) for colistin 8-fold, making the bacteria resistant. Engineered pitA/phoQ and pitA/pmrB double mutants had higher MICs than single mutants, demonstrating additive effects on colistin susceptibility. Single carB and eno mutations did not increase the MIC suggesting that their effect is dependent on the presence of other mutations. Many of the resistant mutants had increased susceptibility to β-lactams and lower growth rates than the parental strain demonstrating that colistin resistance can impose a fitness cost. Two hundred and fourteen P. aeruginosa isolates from a range of sources were tested and 18 (7.8%) were colistin resistant. Sequence variants in genes identified by experimental evolution were present in the 18 resistant isolates and may contribute to resistance. Overall our results identify pitA mutations as novel contributors to colistin resistance and demonstrate that resistance can reduce fitness of the bacteria.

Background Balloon test occlusion (BTO) with adjunctive single‐photon emission computed tomography has been used to predict tolerance after permanent internal carotid artery occlusion. Anatomic characteristics of the cerebral circulation might predict BTO outcomes and identify patients susceptible to test failure. Methods We performed a single‐center retrospective analysis of patients who underwent internal carotid artery BTO from July 2013 to June 2020. Patients who passed the clinical BTO underwent single‐photon emission computed tomography imaging; technetium‐99m‐ethyl cysteinate dimer was injected intravenously after 15 to 30 minutes of occlusion and induced hypotension. The diameter of the vessels of the circle of Willis was measured angiographically. Single‐photon emission computed tomography imaging hypoperfusion severity was classified as none, mild, low intermediate, high intermediate, and severe. A threshold vessel diameter with most predicted accuracy for BTO failure was created using the Youden index. The threshold value was tested in a logistic regression for prediction of BTO failure and accuracy as represented with a receiver operator curve. Results Fifty‐seven patients underwent BTO. Neoplasia was the most common indication (n=43, 75%). Twelve (21.1%) patients failed the clinical BTO. Contralateral dominant vertebral artery (P=0.02), smaller anterior communicating artery (ACom; P=0.002), and ipsilateral posterior communicating artery (P=0.03) diameters were correlated with clinical BTO failure. Smaller ACom was most predictive with an area under the curve of 0.907. The Youden index identified an ACom diameter threshold of 1.1 mm, with a sensitivity of 91.7% and specificity of 77.8% (odds ratio, 0.026 [95% CI, 0.003–0.226]; receiver operating characteristic, 0.847) for predicting BTO failure. Patients with severe single‐photon emission computed tomography asymmetry had significantly smaller‐caliber ACom arteries (ACom median diameter, 0.95 versus 1.4 mm; P=0.0073). Conclusions Angiographic findings can be used to predict BTO results. A small ipsilateral posterior communicating artery, and more significantly, a small ACom (

Chordomas are a locally invasive, low-grade, CNS malignancy that are primarily found in the skull base, spine, and sacrum. They are thought to be derived from notochordal remnants and remain a significant clinical challenge due to their local invasiveness, resistance to chemoradiation, and difficulty in achieving a complete resection. Adjuvant therapy such as proton beam therapy is critical in preventing recurrence in patients who are at high risk, however this treatment is associated with increased risk of complication. Currently, intraoperative observation and imaging findings are used to determine recurrence and success of gross total resection. These methods can be unreliable due to limited operative view, bony and soft tissue involvement, and complex post-operative changes on MRI. Earlier detection of incomplete resection or recurrence will allow for earlier ability to intervene and potentially improve patient outcomes. Circulating-tumor DNA (ctDNA) is cell-free DNA that is released by tumor cells as they undergo cellular turn-over. Monitoring ctDNA has been shown to be more sensitive at predicting residual tumor than imaging in numerous solid malignancies. Furthermore, ctDNA could be detected earlier in peripheral blood as opposed to imaging changes, allowing for earlier intervention. In this review, we intend to give a brief overview of the current state of molecular diagnosis for skull base chordomas. We will then discuss current advances in the utilization of ctDNA for the management of CNS pathologies such as glioblastoma (GBM) and brain metastases. We will also discuss the role ctDNA has in the management of non-CNS pathologies such as osteosarcoma and Ewing sarcoma (EWS). Finally, we will discuss potential implications of ctDNA monitoring for chordoma management.

This report describes a case of pituitary apoplexy with rapidly evolving hemorrhage in a 74-year-old female with coronavirus disease 2019 (COVID-19) disease. The patient presented with severe headache and mild respiratory symptoms, with laboratories concerning for pituitary hypofunction. Brain imaging demonstrated a sellar mass concerning for a pituitary adenoma with ischemic apoplexy. She subsequently developed visual deficits within 24 hours of presentation, and repeat imaging demonstrated evolving hemorrhage and new mass effect on the optic chiasm. She was successfully managed with urgent endoscopic endonasal surgery despite her COVID-19 positive status by taking special intraoperative precautions to mitigate SARS-CoV2 transmission risk. Only a handful of cases of pituitary apoplexy have been reported in association with COVID-19 disease, and even fewer reports exist of endonasal procedures in such cases. We discuss the potential implication of COVID-19 in the occurrence of pituitary apoplexy, in addition to the safety and success of endonasal surgery in this population.

Introduction: The evolution of cavernous sinus meningiomas (CSMs) might be unpredictable and the efficacy of their treatments is challenging due to their indolent evolution, variations and fluctuations of symptoms, heterogeneity of classifications and lack of randomized controlled trials. Here, a dedicated task force provides a consensus statement on the overall management of CSMs. Research question: To determine the best overall management of CSMs, depending on their clinical presentation, size, and evolution as well as patient characteristics. Material and methods: Using the PRISMA 2020 guidelines, we included literature from January 2000 to December 2020. A total of 400 abstracts and 77 titles were kept for full-paper screening. Results: The task force formulated 8 recommendations (Level C evidence). CSMs should be managed by a highly specialized multidisciplinary team. The initial evaluation of patients includes clinical, ophthalmological, endocrinological and radiological assessment. Treatment of CSM should involve experienced skull-base neurosurgeons or neuro-radiosurgeons, radiation oncologists, radiologists, ophthalmologists, and endocrinologists. Discussion and conclusion: Radiosurgery is preferred as first-line treatment in small, enclosed, pauci-symptomatic lesions/in elderly patients, while large CSMs not amenable to resection or WHO grade II-III are candidates for radiotherapy. Microsurgery is an option in aggressive/rapidly progressing lesions in young patients presenting with oculomotor/visual/endocrinological impairment. Whenever surgery is offered, open cranial approaches are the current standard. There is limited experience reported about endoscopic endonasal approach for CSMs and the main indication is decompression of the cavernous sinus to improve symptoms. Whenever surgery is indicated, the current trend is to offer decompression followed by radiosurgery.

Objective: Neck metastases are a poor prognostic factor in olfactory neuroblastoma (ONB). Pathologic dural invasion (pathDI) may increase the risk of neck metastases due to invasion of dural lymphatics. We aim to evaluate the prognostic value of pathDI in predicting rates of neck metastases and recurrence using a large, multicenter database of ONB patients., Data Sources: Retrospective review of a prospective, multicenter database of electronic health records of all patients who presented with ONB between 2005 and 2021 at nine tertiary academic care centers within North America., Review Methods: Clinicopathologic features including modified Kadish staging systems, margin status, treatment modalities, Hyams grading, follow-up time, and survival., Results: Of 258 ONB patients, 189 patients met the inclusion criteria. The 10-year neck recurrence-free survival (neck-RFS) rates were 85.7% (75.6‒97.3) and 61.8% (47.9‒79.8) for patients without and with pathDI, respectively (p = 0.018). Time-to-event multivariable regression analysis found pathDI to have an odds ratios of 9.7 (95% confidence interval [CI] 1.2-80.4, p = 0.04) for neck-RFS and 9.5 for RFS at any site (95% CI 1.1-83.3, p = 0.04)., Conclusion: In multivariable analysis, the presence of pathDI appears to be the strongest predictor of neck recurrence and recurrence at any site. Future studies exploring the benefit of elective neck dissection or radiation for patients with pathDI may impact disease management., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background and Objective: Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated., Methods: Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses., Results: Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm 3 vs 0.49 ± 1.17 cm 3 , P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis., Conclusion: This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Aim: To assess the knowledge, attitudes and practices of Registered Nurses working in residential aged care facilities pertaining to pain management for residents living with dementia., Background: Sub-optimal pain management continues for people living with dementia in residential aged care. Registered Nurses are the pivotal staff responsible for complex assessment and management of people residing in residential aged care facilities., Design and Methods: :This integrative literature review was informed by Whittemore (2005). Searching and screening followed the PRISMA guidelines., Results: Thirteen papers were identified, the major themes identified were gaps in knowledge and skills, uncertainty of assessment, and delays in treatment., Conclusion: Registered Nurses require education on pain management for people living with dementia in residential aged care. Broader issues in residential aged care contribute to the problem and require examination. Research pertaining to Registered Nurses' roles pain management for residents living with dementia is required.

Background: With modern treatment paradigms, olfactory neuroblastoma (ONB) has favorable overall survival (OS); however, the incidence of recurrence remains high. The primary aims of this study were to delineate the prognosis of recurrence of ONB and explore how recurrence subsites are associated with OS, disease-specific survival (DSS), and further recurrence., Methods: A retrospective chart review of ONB cases from nine academic centers between 2005 and 2021 was completed. Tumor characteristics, recurrence subsites, timelines to recurrence, additional recurrences, and survival estimates were determined using descriptive and time-to-event analyses., Results: A final cohort of 233 patients was identified, with 70 (30.0%) patients recurring within 50.4 (standard deviation ±40.9) months of diagnosis on average, consisting of local (50%), neck (36%), intracranial (9%), and distant (6%) recurrence. Compared with subjects without recurrence, patients with recurrence had significantly different primary American Joint Committee on Cancer T stage (p < 0.001), overall stage (p < 0.001), and modified Kadish scores (p < 0.001). Histopathology identified that dural involvement and positive margins were significantly greater in recurrent cases. First recurrence was significantly associated with worse 5-year DSS (hazard ratio = 5.62; p = 0.003), and subjects with neck or local recurrence had a significantly better DSS compared to intracranial or distant recurrence., Conclusions: Recurrent cases of ONB have significantly different stages and preoperative imaging factors. Patients with local or neck recurrence, however, have better DSS than those with intracranial or distant recurrence, independent of initial tumor stage or Hyams grade. Identifying specific factors that confer an increased risk of recurrence and DSS is important for patient counseling in addition to surveillance planning., (© 2024 ARS‐AAOA, LLC.)

This paper presents a novel adaptation of the conventional approximate Bayesian computation sequential Monte Carlo (ABC-SMC) sampling algorithm for parameter estimation in the presence of uncertainties, coined combinatorial ABC-SMC. Inference of this type is used in situations where there does not exist a closed form of the associated likelihood function, which is replaced by a simulating model capable of producing artificial data. In the literature, conventional ABC-SMC is utilised to perform inference on continuous parameters. The novel scheme presented here has been developed to perform inference on parameters that are high-dimensional binary, rather than continuous. By altering the form of the proposal distribution from which to sample candidates in subsequent iterations (referred to as waves), high-dimensional binary variables may be targeted and inferred by the scheme. The efficacy of the proposed scheme is demonstrated through application to vibration data obtained in a structural dynamics experiment on a fibre-optic sensor simulated as a finite plate with uncertain boundary conditions at its edges. Results indicate that the method provides sound inference on the plate boundary conditions, which is validated through subsequent application of the method to multiple vibration datasets. Comparisons between appropriate forms of the metric function used in the scheme are also developed to highlight the effect of this element in the schemes convergence.

Vestibular schwannomas (VS) are the most common tumor of the skull base with available treatment options that carry a risk of iatrogenic injury to the facial nerve, which can significantly impact patients' quality of life. As facial nerve outcomes remain challenging to prognosticate, we endeavored to utilize machine learning to decipher predictive factors relevant to facial nerve outcomes following microsurgical resection of VS. A database of patient-, tumor- and surgery-specific features was constructed via retrospective chart review of 242 consecutive patients who underwent microsurgical resection of VS over a 7-year study period. This database was then used to train non-linear supervised machine learning classifiers to predict facial nerve preservation, defined as House-Brackmann (HB) I vs. facial nerve injury, defined as HB II-VI, as determined at 6-month outpatient follow-up. A random forest algorithm demonstrated 90.5% accuracy, 90% sensitivity and 90% specificity in facial nerve injury prognostication. A random variable (rv) was generated by randomly sampling a Gaussian distribution and used as a benchmark to compare the predictiveness of other features. This analysis revealed age, body mass index (BMI), case length and the tumor dimension representing tumor growth towards the brainstem as prognosticators of facial nerve injury. When validated via prospective assessment of facial nerve injury risk, this model demonstrated 84% accuracy. Here, we describe the development of a machine learning algorithm to predict the likelihood of facial nerve injury following microsurgical resection of VS. In addition to serving as a clinically applicable tool, this highlights the potential of machine learning to reveal non-linear relationships between variables which may have clinical value in prognostication of outcomes for high-risk surgical procedures., (© 2024. The Author(s).)

Importance: Current olfactory neuroblastoma (ONB) staging systems inadequately delineate locally advanced tumors, do not incorporate tumor grade, and poorly estimate survival and recurrence., Objective: The primary aims of this study were to (1) examine the clinical covariates associated with survival and recurrence of ONB in a modern-era multicenter cohort and (2) incorporate Hyams tumor grade into existing staging systems to assess its ability to estimate survival and recurrence., Design, Setting, and Participants: This retrospective, multicenter, case-control study included patients with ONB who underwent treatment between January 1, 2005, and December 31, 2021, at 9 North American academic medical centers., Intervention: Standard-of-care ONB treatment., Main Outcome and Measures: The main outcomes were overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) as C statistics for model prediction., Results: A total of 256 patients with ONB (mean [SD] age, 52.0 [15.6] years; 115 female [44.9%]; 141 male [55.1%]) were included. The 5-year rate for OS was 83.5% (95% CI, 78.3%-89.1%); for DFS, 70.8% (95% CI, 64.3%-78.0%); and for DSS, 94.1% (95% CI, 90.5%-97.8%). On multivariable analysis, age, American Joint Committee on Cancer (AJCC) stage, involvement of bilateral maxillary sinuses, and positive margins were associated with OS. Only AJCC stage was associated with DFS. Only N stage was associated with DSS. When assessing the ability of staging systems to estimate OS, the best-performing model was the novel modification of the Dulguerov system (C statistic, 0.66; 95% CI, 0.59-0.76), and the Kadish system performed most poorly (C statistic, 0.57; 95% CI, 0.50-0.63). Regarding estimation of DFS, the modified Kadish system performed most poorly (C statistic, 0.55; 95% CI, 0.51-0.66), while the novel modification of the AJCC system performed the best (C statistic, 0.70; 95% CI, 0.66-0.80). Regarding estimation of DSS, the modified Kadish system was the best-performing model (C statistic, 0.79; 95% CI, 0.70-0.94), and the unmodified Kadish performed the worst (C statistic, 0.56; 95% CI, 0.51-0.68). The ability for novel ONB staging systems to estimate disease progression across stages was also assessed. In the novel Kadish staging system, patients with stage VI disease were approximately 7 times as likely to experience disease progression as patients with stage I disease (hazard ratio [HR], 6.84; 95% CI, 1.60-29.20). Results were similar for the novel modified Kadish system (HR, 8.99; 95% CI, 1.62-49.85) and the novel Dulguerov system (HR, 6.86; 95% CI, 2.74-17.18)., Conclusions and Relevance: The study findings indicate that 5-year OS for ONB is favorable and that incorporation of Hyams grade into traditional ONB staging systems is associated with improved estimation of disease progression.

Objective  The aim of this work was the development of an augmented reality system including the functionality of conventional surgical navigation systems. Methods  An application software for the Augmented Reality System HoloLens 2 from Microsoft was developed. It detects the position of the patient as well as position of surgical instruments in real time and displays it within the two-dimensional (2D) magnetic resonance imaging or computed tomography (CT) images. The surgical pointer instrument, including a pattern that is recognized by the HoloLens 2 sensors, was created with three-dimensional (3D) printing. The technical concept was demonstrated at a cadaver skull to identify anatomical landmarks. Results  With the help of the HoloLens 2 and its sensors, the real-time position of the surgical pointer instrument could be shown. The position of the 3D-printed pointer with colored pattern could be recognized within 2D-CT images when stationary and in motion at a cadaver skull. Feasibility could be demonstrated for the clinical application of transsphenoidal pituitary surgery. Conclusion  The HoloLens 2 has a high potential for use as a surgical navigation system. With subsequent studies, a further accuracy evaluation will be performed receiving valid data for comparison with conventional surgical navigation systems. In addition to transsphenoidal pituitary surgery, it could be also applied for other surgical disciplines., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Objective: Skull base chordoma is a rare and locally destructive malignancy which presents unique therapeutic challenges. While achieving gross total resection (GTR) confers the greatest survival advantage, the role of adjuvant radiotherapy (RT) for patients who receive GTR remains unclear in the absence of prospective trials. Here, we aim to assess the effect of RT on survival outcomes in skull base chordoma patients who receive GTR by utilizing the Surveillance, Epidemiology, and End Results (SEER) database., Methods: Patients with diagnostic, primary site, and resection codes specific for chordoma, skull base, and GTR, respectively, were queried in the SEER database (2000-2018). Kaplan-Meier curves (log-rank test) were constructed and Cox proportional hazards models were used to assess survival outcomes., Results: A total of 115 skull base chordomas undergoing GTR were identified, of which 37 (32%) received no RT and 78 (68%) received RT. Median follow-up was 55.00 months (range: 0.00-227.00). Overall survival (OS) of patients with GTR was 85% and 70% at 5 and 10 years, respectively. Multivariate Cox proportional hazard analysis among chordoma patients undergoing GTR found age ≥65 (P < 0.01) was associated with poorer OS outcomes. RT appeared to trend toward offering benefit in terms of OS in patients after GTR, however this did not achieve statistical significance in the adjusted model (HR = 0.51, CI = 0.23-1.16, P = 0.09). When comparing, disease-specific survival was also not improved in patients undergoing RT (HR = 0.58, CI = 0.23-1.46, P = 0.25)., Conclusions: It remains unclear whether RT after GTR of chordoma improved survival outcomes among SEER database patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives  Pituitary tumor treatment is hampered by the relative rarity of the disease, absence of a multicenter collaborative platform, and limited translational-clinical research partnerships. Prior studies offer limited insight into the formation of a multicenter consortium. Design  The authors describe the establishment of a multicenter research initiative, Registry of Adenomas of the Pituitary and Related Disorders (RAPID), to encourage quality improvement and research, promote scholarship, and apply innovative solutions in outcomes research. Methods  The challenges encountered during the formation of other research registries were reviewed with those lessons applied to the development of RAPID. Setting/Participants  RAPID was formed by 11 academic U.S. pituitary centers. Results  A Steering Committee, bylaws, data coordination center, and leadership team have been established. Clinical modules with standardized data fields for nonfunctioning adenoma, prolactinoma, acromegaly, Cushing's disease, craniopharyngioma, and Rathke's cleft cyst were created using a Health Insurance Portability and Accountability Act-compliant cloud-based platform. Currently, RAPID has received institutional review board approval at all centers, compiled retrospective data and agreements from most centers, and begun prospective data collection at one site. Existing institutional databases are being mapped to one central repository. Conclusion  The RAPID consortium has laid the foundation for a multicenter collaboration to facilitate pituitary tumor and surgical research. We sought to share our experiences so that other groups also contemplating this approach may benefit. Future studies may include outcomes benchmarking, clinically annotated biobank tissue, multicenter outcomes studies, prospective intervention studies, translational research, and health economics studies focused on value-based care questions., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Embedded soft sensors can significantly impact the design and control of soft-bodied robots. Although there have been considerable advances in technology behind these novel sensing materials, their application in real-world tasks, especially in closed-loop control tasks, has been severely limited. This is mainly because of the challenge involved with modeling a nonlinear time-variant sensor embedded in a complex soft-bodied system. This article presents a learning-based approach for closed-loop force control with embedded soft sensors and recurrent neural networks (RNNs). We present learning protocols for training a class of RNNs called long short-term memory (LSTM) that allows us to develop accurate and robust state estimation models of these complex dynamical systems within a short period of time. Using this model, we develop a simple feedback force controller for a soft anthropomorphic finger even with significant drift and hysteresis in our feedback signal. Simulation and experimental studies are conducted to analyze the capabilities and generalizability of the control architecture. Experimentally, we are able to develop a closed-loop controller with a control frequency of 25 Hz and an average accuracy of 0.17 N. Our results indicate that current soft sensing technologies can already be used in real-world applications with the aid of machine learning techniques and an appropriate training methodology.

One of the major obstacles to the widespread uptake of data-based Structural Health Monitoring so far, has been the lack of damage-state data for the (mostly high-value) structures of interest. To address this issue, a methodology for sharing data and models between structures has been developed- Population-Based Structural Health Monitoring (PBSHM). PBSHM works on the principle that, if populations of structures are sufficiently similar, or share sections which can be considered similar, then data and models can be shared between them for use in diagnostic inference. The PBSHM methodology therefore relies on two key components: firstly, identifying whether structures are sufficiently similar for successful transfer of diagnostics; this is achieved by the use of an abstract representation of structures. Secondly, machine learning techniques are exploited to effectively transfer information between the structures in a way that improves damage detection and classification across the whole population. Although PBSHM has been conceived to deal with large and general classes of structures, much of the detailed developments presented so far have concerned bridges; the aim of this paper is to provide similarly detailed discussions in the aerospace context. The overview here will examine data transfer between aircraft components, as well as illustrating how one might construct an abstract representation of a full aircraft., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brennan, Gosliga, Gardner, Mills and Worden.)

Objective: Prealbumin levels correlate with overall nutritional status, and low values are associated with poor wound healing. We investigated whether low preoperative prealbumin levels predict risk of endoscopic endonasal skull base surgery (EESBS) reconstruction failure, as demonstrated by postoperative cerebrospinal fluid (CSF) leak and/or infection., Methods: Between October 2018 and February 2020, 98 patients with documented preoperative prealbumin levels were prospectively followed. The incidence of CSF leak and infection in patients with low prealbumin levels (≤20 mg/dL) was compared with those with normal prealbumin levels (>20 mg/dL). Numerous factors previously shown to influence CSF leak rates were assessed. Both univariate and multivariable analyses were performed to identify independent predictive factors., Results: Within this prospectively gathered patient cohort composed of >95% "high-risk" expanded EESBS, 14 of 98 patients (14.3%) experienced a postoperative CSF leak. Factors univariately associated with postoperative complications at the 0.2 level of significance were used in a multivariable model. Low prealbumin levels (≤20 mg/dL) proved to be a strong independent predictive factor associated with a 5-fold increased risk of postoperative CSF leak (odds ratio 5.01, P = 0.01), and postoperative surgical-site infection (P = 0.0009). These associations remained after controlling for multiple other factors, including body mass index, surgical pathology, previous EESBS, risk assessment index, and high- versus low-flow intraoperative CSF leaks., Conclusions: Preoperative prealbumin levels are an independent predictor of EESBS associated CSF leak and infection. Future studies are needed to investigate the utility of screening and correcting prealbumin levels to limit postoperative complications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Patients taking a medicinal product in a homecare setting typically use a medical device to facilitate the injection process. Reductions in wireless connectivity costs, combined with the rapid adoption of smartphones with connectivity to cloud-based services, are enabling these drug delivery devices to now be connected to a digital ecosystem as connected combined products (CCPs). The purposes of this article are to identify the challenges in developing and releasing these products when they straddle different regulatory frameworks and standards and to highlight gaps in the European Union regulations., Methods: Industry subject matter experts from pharmaceutical, medical device, and consultancy companies, who are members of the Medtech & Pharma Platform Association, formed 4 working groups to address current best practice for developing and releasing CCPs and the different relevant regulatory frameworks. The 4 areas studied were clinical and regulatory, usability and human factors engineering, development and life cycle management, and cybersecurity., Findings: Development teams require new skills to create innovative products that have a good safety profile and are simple to use, such as design thinking to understand user needs and systems engineering to manage complexity and ensure interoperability. Risk management process should integrate cybersecurity, data privacy, and data integrity, whereas design control processes should enable asynchronous development cycles for hardware and software components. Regulatory frameworks exist for individual components within the CCP. However, for a complex product, regulatory guidance is needed when combining components with different risk and safety profiles and to ensure that the responsibilities and liabilities of companies contributing components are clear. The efficient management of software changes and product updates, as well as dealing with end-of-life hardware and backward compatibility to older software versions, needs agile approaches when it comes to regulatory updates., Implications: The regulatory uncertainties and development processes outlined in this article need to be addressed. We call for joint discussions among the various stakeholders in the fields of medicinal products, medical devices, and in vitro diagnostics, as well as standalone software, data protection, and cybersecurity experts, together with regulators and lawmakers in the European Union to meet in focused discussion groups with the aim of devising pragmatic solutions and regulations for the benefit of the sector and hence the patients it serves., Competing Interests: Declaration of Interest All authors hold positions in commercial companies, but they have not received any grant, honoraria, or other compensation to author this article. The study was conceived of, executed on, and written during the authors’ day job. Authors may hold shares and/or stock options in their respective companies. The authors have indicated that they have no other conflicts of interest regarding the content of this article., (Copyright © 2022. Published by Elsevier Inc.)

Objective  The endoscopic endonasal approach (EEA) is commonly employed in skull base surgery for neoplasm resection. While nasal deformity following EEA is described, this study aimed to perform a detailed qualitative and quantitative assessment of the associated saddle nose deformity (SND) in particular. Setting/Participants  This is a retrospective review of 20 adult patients with SND after EEA for resection of skull base tumors over a 5-year period at the University of Pittsburgh Medical Center. Main Outcome Measures  Fifteen measurements related to SND were obtained on pre- and postoperative imaging. Statistical analyses were performed to evaluate differences between pre- and postoperative anatomies. Results  The most common EEA was transsellar. Reconstruction techniques included nine free mucosal grafts alone, eight vascularized nasoseptal flaps (NSFs), one combined free mucosal graft/abdominal fat graft, and one combined NSF/fascia lata graft. Imaging analysis showed a trend toward loss of mean nasal height, nasal tip projection, and nasolabial angle postoperatively. Subgroup analysis showed that patients with NSF reconstruction had a significantly decreased nasal tip projection (1.2 mm, p  = 0.039) and increased alar base width (1.2 mm, p  = 0.046) postoperatively. Patients without functional pituitary microadenomas demonstrated significantly increased nasofrontal angle and decreased nasal tip projection on postoperative imaging, in contrast to those with functional adenomas who had no measurable significant changes. Conclusion  Clinically evident SND does not always lead to significant radiographic changes. This analysis suggests that patients who undergo surgery for indications other than functional pituitary microadenomas or who receive NSF reconstruction develop more marked SND on standard imaging tests., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)